Hyperprolactinemia

By: Edward L. Marut, M.D.

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Hyperprolactinemia is a relatively common cause of menstrual abnormalities and Infertility. It may be accompanied by galactorrhea, a milky or watery nipple discharge either spontaneously present or easily expressed. Blood for aProlactin level should be drawn, along with a TSH level, in any patient with ovulatory or menstrual disturbances, or non-puerperal galactorrhea. Prolactin causes lactation by a direct mammary action and disrupts Ovulation through its suppression of Gonadotropin releasing Hormone (GnRH). The physiologic effects of nursing in causing postpartum amenorrhea are well recognized. The normal ranges for different laboratories may differ, but not by much. The upper limit of normal is around 30 ng/ml. Blood should be drawn in a fasting state in the morning to avoid spurious elevations caused by food intake or time of day. In addition, if the patient is having menstrual cycles, the test should be done within a few days of the period, since Cycle dependent elevations occur as well. The sample should be drawn after the patient has been at rest for at least 15 minutes and prior to any other procedures, since stress readily elevates prolactin to often significantly high levels. While the concern for the source of hyperprolactinemia lies in the presence of a pituitary tumor, there are several other medical conditions that result in high levels.

The use of psychoactive drugs, especially antipsychotics and antidepressants, can elevate prolactin levels. Metoclopromide (Reglan) is used in gastrointestinal disorders and raises prolactin levels. Other antihypertensives, antibiotics and hormonal preparations may have similar effects, and should be ruled out as the cause. The control of prolactin secretion, which is pulsatile, is tonic inhibition by the neurotransmitter dopamine, and many of these drugs work by interfering with the dopamine effect. The levels are usually not in the range of those produced by a prolactinoma, and treatment is problematic, since the beneficial effects of the offending medication can be reversed by treatment of the elevated prolactin. Primary hypothyroidism also can result in hyperprolactinemia. Low thyroid hormone production by the thyroid gland results in the typical elevation of TSH (thyroid-stimulating hormone), which is stimulated by negative feedback on hypothalamic TRF (thyrotropin-releasing factor). TRF also stimulates prolactin release from the pituitary, either by a direct effect on prolactin-secreting cells, or by reducing dopamine effect. Treatment of the thyroid deficiency should normalize the prolactin level.

Local breast Stimulation can elevate prolactin levels, including voluntary stimulation, as well as chest wall lesions including tumors or inflammatory processes such as zoster, that stimulate thoracic nerves. Vasoactive intestinal peptide (VIP) is the likely mediator for prolactin effects from breast stimulation.

Chronic or acute liver and renal disease can be associated with hyperprolactinemia, due to the impaired clearance from the bloodstream.

Chronic or acute stress states will elevate prolactin to moderately high levels, and will often normalize on repeat measurements under less stressful conditions.

Macroprolactinemia is an unusual cause of hyperprolactinemia, and has no pathologic effects; it is due to polymerization of smaller molecules of prolactin and failure to bind to its receptors.

If prolactin levels exceed 100 ng/ml, there is suspicion of a prolactinoma, which is best diagnosed by an MRI. If a microprolactinoma or microadenoma (<10 mm) is present, further assessment is usually not necessary, while a macroprolactinoma or macroadenoma (10+ mm) calls for ophthalmologic (for visual field testing) or neurosurgical consultation (if neurologic symptoms are present), although surgery is rarely indicated in 2009 except in extreme cases. A prolactin level over 250 ng/ml suggests a macroadenoma. The likelihood of a microadenoma is small with moderately elevated prolactin levels, but a tumor can be associated with any elevation, and it never hurts to document the pituitary anatomy to have a baseline.

The treatment of hyperprolactinemia depends on the degree of elevation, the associated symptoms, and the fertility wishes of the patient. A woman with normal menses but annoying galactorrhea would be a candidate for pharmacotherapy, as would a woman with hypoestrogenic amenorrhea, or one attempting pregnancy. The hypogonadotropism induced by hyperprolactinemia can lead to osteoporosis, among other complications of hypoestrogenism. On the other hand, relatively mild elevations, even in the presence of a microadenoma can be followed expectantly. Menstrual irregularity can safely be treated by hormonal contraceptives, which usually do not affect the levels adversely.

The mainstay of medical treatment is bromocryptine (Parlodel). This drug is a dopamine agonist, which stimulates the dopamine receptors in the pituitary and almost always normalizes the prolactin level, and corrects the related problems. Prolactinomas often shrink during treatment, and in fact sometime completely regress. Interestingly, spontaneous regression is possible as well. Bromocryptine has been shown to be safe in pregnancy, although once the pregnancy is established the drug can be withdrawn. Parlodel is started at 1.25 mg daily and is gradually increased up to 5 mg bid if levels do not come down. The normal expansion of the pituitary in pregnancy with normally high prolactin levels may occasionally cause progression of the tumor, although this is rare except with macroadenomata. Medication can be reinstituted during the pregnancy if symptoms such as headache or visual symptoms occur. Other dopamine agonists such as cabergoline (Dostinex) have been approved for use. Dostinex has a longer half-life and purports to have fewer side effects associated with dopamine agonists, such as nasal congestion, dizziness and hypotension. . Dostinex starts at 0.25 mg twice a week and may be increased up to 1 mg twice a week. There have been reports of the longer acting dopaminergic agents causing cardiac valve disease due to receptors in the heart; this seems to largely occur with long-term use and high doses. Vaginally administered Parlodel has been used to avoid some of the side effects as well. As usual, the lowest dose for the shortest time is the correct path to follow. Pergolide, a long-acting dopaminergic agent, was taken off the market in 2007 because of the cardiac association.

There are some tumors that do not respond to medical treatment; sometimes they are not prolactinomas at all, but non-functional tumors that cause disruption of the dopamine pathways in the pituitary and may require surgery. Resistance of the prolactin level to normalization may be an indication for surgery, especially if there are eye or neurological symptoms.

The physicians of Fertility Centers of Illinois always welcome referrals for hyperprolactinemia, as well as all reproductive endocrine conditions, and are happy to answer any questions from referring physicians on patient management and treatment.